Synthesis and disproof of the structure proposed for the tetrahydrofuranol isolated from Michelia compressa var. lanyuensis (Magnoliaceae)

The previously proposed structure for a tetrahydrofuranol isolated from the leaves of Michelia compressa var. lanyuensis (Magnoliaceae) was synthesised in an enantiopure form using diethyl D-tartarate as the starting material. The synthetic sample showed spectroscopic data incompatible with those for the natural product and thus unequivocally disproved the previously assigned structure.     

The Macrocyclic Spermidine Alkaloid (−)‐(S)‐Neoperiphylline: Revision of the Structure Based on the Total Synthesis

The total synthesis of the two isomeric macrocyclic enamides 2 and 17 is described. The precursor 14 was synthesized by means of template‐assisted macrocyclization (Scheme 2). Isomerization of 14 in the presence of [Fe(CO)₅] gave 2 and 17 (Scheme 4). Structure 2 was previously assigned to the alkaloid neoperiphylline. However, the synthetic 2 showed completely different properties compared to the earlier described data of the natural compound. Surprisingly, analytical data of the second synthetic product 17 were very close to those of the natural neoperiphylline. We conclude that the previously assigned structure of neoperiphylline is erroneous and should be corrected to that of (?)‐(4S,12Z)‐4‐phenyl‐9‐[(2E)‐3‐phenylprop‐2‐enoyl]‐1,5,9‐triazacyclotridec‐12‐en‐2‐one ( 17 ).     

Catalysis‐Based Total Synthesis of Putative Mandelalide A

A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A ( 1 ) is disclosed. Specifically, an iridium‐catalyzed two‐directional Krische allylation and a cobalt‐catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal‐acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11‐epi‐ 1 deviate from those of the natural product, which implies a subtle but deep‐seated error in the original structure assignment.     

Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters

Two recently identified natural phenolic homobenzyl esters, isolated from Phragmipedium calurum (an orchid) and Eupatorium fortunei TURCZ (a perennial herb in the Asteraceae family), respectively, were synthesized in enantiopure forms. By comparison of the optical rotations for the synthetic and the natural samples, the absolute configurations for the natural products were reliably assigned. The synthesis also enables establishment of the absolute configuration of a closely related natural homobenzyl alcohol and provided for the first time complete physical and spectroscopic data for two other natural homobenzyl esters.     

Pyrolysis of polyisoprenes. I. Differentiation between natural and synthetic cis-1,4-polyisoprenes

Two methods of differentiating between natural rubber and synthetic cis-1,4-polyisoprenes have been examined. Both techniques depend on the presence of Ziegler-Natta catalyst residues in the synthetic polymers. The major pyrolysis product of cis-1,4-polyisoprenes at 350°C is 1-methyl-4-(1-methylethenyl)cyclohexene. This can undergo disproportionation to yield 1-methyl-4-(1-methylethyl)benzene and methyl-(1-methylethyl)cyclohexenes. It is this disproportionation reaction, catalyzed by Ziegler-Natta catalyst residues or by carbon black, that is responsible for the different product ratios obtained on pyrolysis of natural rubber and Ziegler-Natta catalyzed cis-1,4-polyisoprenes. Lithium alkyl-polymerized polyisoprenes undergo this secondary disproportionation reaction only in the presence of carbon black. Derivative thermogravimetric traces of black-filled sulfur vulcanizates of natural rubber and synthetic polyisoprenes are significantly different because polymerization catalyst residues promote cyclization of the polymer.     

A total synthesis of (S)-(+)-ipalbidine

(S)-(+)-Ipalbidine, [α]²⁵_D+ 54.1° (c = 1, ethanol) as hydrobromide, was synthesized from natural (S)-proline with retention of configuration. The hydrobromide of the synthetic product was identical in all respects with that of the optically active natural ipalbidine isolated from the Chinese species Ipomoea hardwickii Hemsl.     

Total Synthesis,Stereochemical Revision,and Biological Assessment of Iriomoteolide-2a

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2 – 5 as candidates for the correct structure. Accordingly, total syntheses of 2 – 5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2 – 5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5 /ent- 5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent- 5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.     

First Total Synthesis,Structure Revision,and Natural History of the Smallest Cytochalasin: (+)‐Periconiasin G

The total synthesis of the smallest cytochalasin isolated so far, periconiasin G, which bears a seven‐membered ring in lieu of the usual macrocycle, has been performed from both enantiomers of citronellal, relying on an intramolecular Diels–Alder reaction in favor of the natural endo stereochemistry. We show that, among the four synthesized stereoisomers, including the exo isomers, the one matching the NMR data of the natural product was not that assigned in the original report, imposing structure revision. The natural product, previously isolated from a plant‐mutualistic fungus, was biologically investigated taking into account its natural history, showing significant effects against the phytopathogenic fungus Botrytis cinerea and thus opening new opportunities in combating this pest.     

Structure Determination of Brominated Morphinan-6-ones by 13C-NMR. Spectroscopy: A novel closure of the oxygen bridge using 4-acetoxymorphinan-6-ones

Bromination of (?)-4-hydroxy-N-methylmorphinan-6-one ( 3 ), prepared from natural morphine, with 1 mol of bromine in acetic acid, afforded the 1-bromo ketone 5 . The structure of 5 was assigned by ¹³C-NMR.spectroscopy, and confirmed by X-ray diffraction analysis of its hydrobromide salt. It is suggested that monobromination of synthetic (±)-2,4-dihydroxy-N-formylmorphinan-6-one ( 7 ) takes in principle a similar course, although the ¹³C-NMR.spectrum of the primary reaction product 9 could not be measured because of insolubility in commonly used solvents. Monobromination of (?)-4-acetoxy-N-formylmorphinan-6-one ( 12 ) of the natural series, and of (±)-2,4-diacetoxy-N-formylmorphinan-6-one ( 8 ) of the synthetic series, followed by treatment of the monobrominated ketones with potassium carbonate in methanol resulted in closure of the O-bridge, and afforded after acid hydrolysis, the corresponding 4,5-epoxy-morphinan-6-ones (?)- 16 and (±)- 17 respectively. This variation of the ring closure reaction represents a novel and convenient method to convert 4-hydroxymorphinan-6-ones into their corresponding 4,5-epoxymorphinan-6-ones, without involving aromatic bromination and with only 1 mol of bromine.     

Convergent Total Syntheses of (−)‐Rubriflordilactone B and (−)‐pseudo‐Rubriflordilactone B

A highly convergent strategy for the synthesis of the natural product (?)‐rubriflordilactone B, and the proposed structure of (?)‐pseudo‐rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo‐rubriflordilactone B and provides a robust platform for further synthetic and biological investigations.     

Total Synthesis of the Proposed Structure of Ardimerin,and Proposal for its Structural Revision

We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.     

First Total Synthesis of Desmosdumotin C †

Abstract

Desmosdumotin C (1), a novel compound isolated from the roots of Desmos dumosus, was synthesized from 2,4,6‐trihydroxyacetophenone (2), confirming the assigned structure of the natural product.     

Total Synthesis of Putative Chagosensine

The marine macrolide chagosensine is the only natural product known to date that embodies a Z,Z‐configured chloro‐1,3‐diene unit. This distinguishing substructure was prepared by a sequence of palladium‐catalyzed 1,2‐distannation of an alkyne precursor, regioselective Stille cross‐coupling at the terminus of the resulting bisstannyl alkene with an elaborated alkenyl iodide, followed by chloro‐destannation of the remaining internal site. The preparation of the required substrates centered on cobalt‐catalyzed oxidative cyclization reactions of hydroxylated olefin precursors, which allowed the 2,5‐trans‐disubstituted tetrahydrofuran rings, embedded into each building block, to be formed with excellent selectivity. The highly strained macrolactone could ultimately be closed under forcing Yamaguchi conditions. Comparison of the spectral data of the synthetic sample with those of authentic chagosensine methyl ester confirmed that the structure of this intriguing compound has been mis‐assigned by the isolation team.     

Total Synthesis of 4″‐O‐Acetylmananthoside B,Part I: Synthesis and Tentative Ozonolysis of a Cyclohexadiene Derivative

A cyclohexadiene derivative cis‐N,N‐diethyl‐2‐benzyloxymethyl‐1,2‐dihydrobenzamide 8 was constructed from γ‐butyrolactone I for the total synthesis of a natural product 4″‐O‐acetylmananthoside B, which was reported to display significant cytotoxic activity. Preliminary ozonolysis of 8 for further synthetic purposes was also carried out.     

Total Synthesis and Absolute Configuration of Epicoccamide D,a Naturally Occurring Mannosylated 3‐Acyltetramic Acid

The endofungal metabolite epicoccamide D was synthesised in eighteen steps and 17 % yield as the first member of the family of natural glycotetramic acids. The modular character of the synthesis opens access also to analogues featuring different sugars and spacers. It comprises several high‐yielding key steps. The β‐D ‐mannosyl group was introduced by using an α‐D ‐glucosyl imidate donor with subsequent oxidative‐reductive epimerisation at C‐2′. The pyrrolidine ring was closed quantitatively by a Lacey‐Dieckmann condensation of an N‐(β‐ketoacyl)‐N‐methyl alaninate. The resulting 3‐[ω‐(β‐D ‐mannosyl)octadec‐2‐enoyl]tetramic acid was hydrogenated in the presence of the rhodium catalyst (R,R)‐[Rh(Et‐DUPHOS)][BF₄] to establish the (7S)‐stereocentre. This was possible only after blocking the acyltetramic acid as a BF₂‐chelate to prevent capture of the metal catalyst. We also assigned the hitherto unknown configuration of the natural product as being 5S,7S by comparison of its ¹³C NMR spectroscopic and optical rotation data with those of our two synthetic 5S,7R/S‐diasteromers.     

Preparation of phenyl‐modified natural rubber in latex stage

Phenyl‐modified natural rubber was prepared in latex stage by bromination of deproteinized natural rubber followed by Suzuki‐Miyaura cross‐coupling reaction. First, the bromination of natural rubber was carried out using N‐bromosuccinimide in latex stage. The bromine atom content increased as amount of N‐bromosuccinimide increased. Second, the allylic bromine atom was replaced with a phenyl group using phenyl boronic acid in the presence of a palladium catalyst, according to the Suzuki‐Miyaura cross‐coupling reaction in latex stage. The resulting products were characterized by nuclear magnetic resonance (NMR) spectroscopy. Signal at 7.13 ppm was assigned to the phenyl group of the product, while signals at 3.98, 4.14, and 4.44 ppm were assigned to the remaining allylic brominated cis‐1,4‐isoprene units. The estimated phenyl group content and the conversion of the Suzuki‐Miyaura cross‐coupling reaction were 1.32 and 23.7 mol%, respectively. Glass transition temperature (T_g) of deproteinized natural rubber increased from ?62°C to ?46.7°C, when the phenyl group was introduced into the rubber.     

Total Synthesis of (−)-(2R)-Dihydromyricoidine

An asymmetric synthesis of the spermidine alkaloid (?)-(2R)-dihydromyricoidine ( 5 ) was performed by employing two ring-enlargement reactions. The chiral center was introduced by a diastereoselective Michael addition of perhydropyridazine ( 7 ) to the α,β-unsaturated ester 6 . The (Z)-C?C bond was obtained by a selective Wittig reaction. The synthetic compound 5 was found to have a negative value for the specific rotation. This is in contrast to that of the natural product reported in the literature. Therefore, as an outcome of this synthesis, the absolute configuration of the natural alkaloid should be inverted to be as shown in structure V .     

Structure-Pattern-Based Total Synthesis

In this article the concept of structure-pattern-recognition and its application to total synthesis is summarized. By applying this synthetic strategy to the two biogenetically unrelated natural product families Sarpagine and Stemona alkaloids, a drastic increase of synthetic efficiency could be achieved. To highlight its potential, this strategy is compared with some elegant target-oriented syntheses. The importance of strategic planning and synthesis design is clearly demonstrated.     

Scobidiynediol的合成及绝对构型

本文报道了以光学活性乳酸为手性元对目标化合物的所有可能的四个异构体所进行的合成。根据合成样品与天然产物的核磁及旋光数据比较，标题化合物的相对及绝对构型都得以完全确立，其完整结构定为(2S,3S)-4,6-庚二炔-2,3-二醇。     

Elucidation of the absolute configuration of rhizopine by chiral supercritical fluid chromatography and vibrational circular dichroism

The absolute configuration of rhizopine, an opine‐like natural product present in nitrogen‐fixing nodules of alfalfa infected by rhizobia, is elucidated using a combination of state‐of‐the‐art analytical and semi‐preparative supercritical fluid chromatography and vibrational circular dichroism spectroscopy. A synthetic peracetylated racemate was fractionated into its enantiomers and subjected to absolute configuration analysis revealing that natural rhizopine exists as a single enantiomer. The stereochemistry of non‐derivatized natural rhizopine corresponds to (1R,2S,3R,4R,5S,6R)‐4‐amino‐6‐methoxycyclohexane‐1,2,3,5‐tetraol.